h e a l t h s a g e s o n d h e i d 2 2 ( 2 0 1 7 ) 1 1 2 e1 2 2

Available online at www.sciencedirect.com

ScienceDirect

journal homepage: http://ees.elsevier.com/hsag/default.asp

Review Article

Ocular allergy

Khathutshelo Percy Mashige

University of KwaZulu-Natal, Discipline of Optometry, Private Bag X54001, Durban, 4000, South Africa

article info abstract

Article history: Aim: To systematically review relevant literature investigating the classification and
Received 30 January 2015 nomenclature, epidemiology and pathophysiological mechanisms, as well as diagnosis and
Accepted 13 July 2016 treatment of ocular allergy.
Available online 27 February 2017 Method: The Medline, PubMed, Elsevier Science Direct, and Google Scholar databases were
used to search for evidence-based literature on ocular allergy.
Keywords: Main outcome measures: Classification and nomenclature, epidemiology and pathophysio-
Ocular allergy logical mechanisms, diagnosis and management of ocular allergy.
Perennial conjunctivitis Results: The search retrieved 5200 number of studies of which 6 met the criteria.
Allergic conjunctivitis Conclusions: While numerous studies regarding pharmacological and immunological
Atopic keratoconjunctivitis research have identified new treatment options, there is a dearth of clinical studies to
Vernal keratoconjunctivitis discover the biomarkers and immune therapeutic management to control sensitisation
Giant papillary conjunctivitis and effector phases of this condition. Given the complexity of this condition due to the
multifactorial nature of the possible aetiologies, rigorous well-designed scientific studies
are needed to determine the exact classification, prevalence and underlying immune
pathological processes of ocular allergy.
Copyright © 2016, The Author. Publishing services by Elsevier B.V. on behalf of Johannesburg
University. This is an open access article under the CC BY-NC-ND license (http://
creativecommons.org/licenses/by-nc-nd/4.0/).

of the causal allergen with the conjunctiva using a series of

1. Introduction protective measures, with medication assisting in controlling
the symptoms produced by the allergic inflammatory process
Ocular allergies encompass a group of hypersensitivity dis- (Chowdhury, 2013; La Rosa et al., 2013).
orders to normally harmless substances, known as allergens There is currently no universal standard nomenclature and
and can be observed as the only dominant presentation of an classification, making an estimation of ocular allergy preva-
allergic sensitisation, or are associated with rhinitis, asthma, lence challenging. In addition, as most ocular allergic diseases
atopic dermatitis or food allergy (Leonardi et al., 2012). The are comorbidities of rhinitis, available prevalence data en-
most common clinical presentations of ocular allergy are compasses both ocular and nasal symptoms, making it
conjunctival hyperaemia (redness) and chemosis (swelling), impossible to separate ocular allergy and allergic rhinitis (La
itching and tearing, and vision loss in severe cases Rosa et al., 2013). Moreover, controversy continues to sur-
(Chowdhury, 2013; Leonardi, De Dominicis, & Motterle, 2007). round the exact pathophysiological mechanisms involved in
Management of this condition is based on minimising contact ocular allergic diseases. The purpose of this paper is therefore

E-mail address: mashigek@ukzn.ac.za.

Peer review under responsibility of Johannesburg University.
http://dx.doi.org/10.1016/j.hsag.2016.07.001
1025-9848/Copyright © 2016, The Author. Publishing services by Elsevier B.V. on behalf of Johannesburg University. This is an open
access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
 h e a l t h s a g e s o n d h e i d 2 2 ( 2 0 1 7 ) 1 1 2 e1 2 2 113

to systematically review scientific and published research were not relevant to the objectives of the review. The flow
studies on the classification and nomenclature, epidemiology chart and check list of the CASP tool used are shown in
and pathophysiological mechanisms, diagnosis and manage- Appendices 1A and 2 respectively. The 6 studies included in
ment of ocular allergy. the synthesis covered all aspects with respect to the classifi-
cation and nomenclature, epidemiology, pathophysiological
mechanisms, diagnosis and treatment of ocular allergy. A
2. Method and scope of review summary of the selected studies is shown in Appendix 1B.

The initial search term was ‘ocular allergy’ by the Information

Specialist (IS). An article was considered for review if it met 3. Classification and nomenclature
the inclusion criteria of reporting on the classification,
nomenclature, epidemiology, pathophysiology, clinical pre- According to the traditional classification of ocular allergy, the
sentation, or an approach to diagnosis and management of six forms are: seasonal (SAC) and perennial allergic conjunc-
ocular allergy. Articles published between 1994 and 2015 years tivitis (PAC), vernal keratoconjunctivitis (VKC), atopic kerato-
in English, and indexed in the following electronic databases conjunctivitis (AKC), contact dermatoconjunctivitis (CDC),
were searched: Medline, PubMed, Elsevier Science Direct, and and giant papillary conjunctivitis (GPC) (Leonardi et al., 2007).
Google Scholar. The standard process for a systematic litera- This traditional classification is based on clinical presentation
ture review was adopted: (Table 1) or on pathophysiology, according to the different
hypersensitivity mechanisms introduced by Gell and Coombs.
1. Titles were reviewed and those which were not relevant Their classification divides allergies into four pathophysio-
were rejected. logical types, namely anaphylaxis (type I), antibody-mediated
2. Abstracts of publications that were not rejected were cytotoxic reactions (type II), immune complex-mediated re-
obtained. actions (type III), and delayed type hypersensitivity (type IV)
3. Two individuals reviewed the abstracts independently and
nchez et al., 2011). However, many hypersensitivity re-
(Sa
rejected further papers that were not eligible. A third in- actions cannot be explained in this context and its use is
dividual adjudicated if there were any differences. therefore no longer recommended (Sa
nchez et al., 2011).
4. Full text of the abstracts selected was obtained. Despite these limitations, the Gell and Coombs's classification
5. Further papers were rejected if, on closer inspection, were is still valid in a few well-defined circumstances.
not relevant or did not provide sufficient detail. Efforts have recently been made to further clarify the
6. Tables for data extraction were prepared. classification and nomenclature of ocular allergy. If different
7. Two people extracted data and compared entries. aspects of the condition are considered, such as its clinical
presentation and duration or the immunopathogenesis, the
The full copies of articles identified by the search, and criteria for ocular allergy may change (Leonardi et al., 2007).
considered to meet the inclusion criteria based on their title, For example, ocular allergies can be classified as ‘intermittent’
abstract and subject descriptors, were obtained for the data or ‘persistent’, and ‘mild’, ‘moderate’ or ‘severe’ depending on
synthesis. Articles identified through reference lists and their evolution and severity. Similarly, symptoms can be
bibliographic searches were also considered for data collec- considered as ‘acute’ or ‘chronic’ and ‘recurrent’ according to
tion based on their title. Two reviewers independently onset and duration, or as ‘follicular’ and ‘papillary conjuncti-
selected articles against the inclusion criteria. Discrepancies vitis’, ‘cicatrising’ and ‘noncicatrising’, emphasising the pre-
in reviewer selections were resolved at a meeting of the re- dominant clinical presentations (Leonardi et al., 2007).
viewers prior the selected articles being retrieved. In 2001, the European Academy of Allergy and Clinical
Immunology (EAACI) and the Nomenclature Review Com-
2.1. Critical appraisal mittee of the World Allergy Committee (WAO) jointly intro-
duced a revised nomenclature that distinguishes between
Identified studies were assessed independently for quality allergic and nonallergic hypersensitivity reactions, with
and validity by two reviewers using the corresponding allergic diseases being further divided into IgE- and non-IgE
checklist from the Critical Appraisal Skills Programme (CASP) hypersensitivities (Johansson et al., 2001, 2004). The advan-
tools (Critical Appraisal Skills Programme, 2014) before being tage of this new classification was that it gave a more sche-
included in the review. Any disagreements that arose between matic immunopathological approach, with IgE-mediated
the reviewers were resolved through discussion and with the ocular allergy being divided into intermittent and persistent
assistance of a third person where required. forms, the latter being classified as VKC and AKC. However, a
The initial search yielded a total of 5200 records, of which serious limitation of this classification is contact dermato-
the Information Specialist (IS) removed 360 duplicates and conjunctivitis (CDC), which is a ‘non-IgE-mediated form of
pre-screened 4840 records. Thereafter 3870 records which localized contact dermatitis, but immunologically different
were not relevant to the scope of the review were removed. from VKC or AKC’ (Leonardi et al., 2007). In addition, ‘contact
The reviewers screened the remaining 970 records and dis- lens-related GPC should be considered as non-IgE mediated,
carded a further 800 records as not meeting the inclusion mechanically related to the lens micro-trauma, which, how-
criteria. A total of 170 full text reports were obtained for ever, shares some immunopathological aspects with VKC’
further assessment, of which 6 articles met the inclusion (Leonardi et al., 2007), which can lead to more confusion. The
criteria and 164 articles were excluded, with reasons, as they above-mentioned limitations prompted the international
114 h e a l t h s a g e s o n d h e i d 2 2 ( 2 0 1 7 ) 1 1 2 e1 2 2

Ocular Inflammation Society (IOIS) to propose a more

Atopic or nonatopic
comprehensive classification that included both the ‘IgE-
mediated’ SAC and PAC and the ‘non-IgE-mediated’ VKC and

Giant papillae
GPC

AKC (Table 1). However, this latest classification system is

Nonallergic

Hyperemia
Persistent

Persistent
unclear, and a new classification system is therefore desir-
able, preferably derived from the varied pathophysiological

Rare
mechanisms operating in the different forms of ocular allergy.
e
Chronic ± intermittent

Chronic ± intermittent
Table 1 e Summary of studies on classification and nomenclature of ocular allergy based on underlying hypersensitivity and clinical presentation.

Erythema, eczema
Non-IgE-mediated

4. Epidemiology
exacerbations

exacerbations
CDC

±Hyperemia

Allergic eye diseases are reported to have dramatically

Nonatopic

Follicles

increased since the year 2000 and are the most common
conditions affecting the external adnexa (Sa
nchez et al., 2011).
e

The epidemiology of ocular allergy has not been sufficiently

investigated to date, and most of the available prevalence data
Eczema þ meibomitis blepharitis

encompasses both ocular and nasal symptoms. For example, a

study in Italy involving 898 new patients visiting an allergy
IgE- and non-IgE-mediated

clinic found that 40% reported symptoms of ocular allergy,

and 66% were also diagnosed with seasonal allergic rhinitis
Neovascularisation
AKC

Papillae þ fibrosis

(Bonini, 2006). A study conducted in Japan found that 90% of

all patients with pollen allergy presented with allergic
±Trantas dots
Adult atopic

±Thickened

conjunctivitis (Takano, Narita, & Kobayashi, 2004). Studies in

Opacities
Chronic

Chronic

Sweden (Hesselmar, Aberg, Eriksson, & Arberg, 2001), Spain

Plaque
Ulcer

(Ibanez & Garde, 2009) and Brazil (Riedi & Rosario, 2010) also
SPK

found the prevalence of ocular allergy among children to be

associated to rhinitis in the majority of the cases. The Inter-
IgE- and non-IgE-mediated
Persistent ± intermittent

Persistent ± intermittent

national Study of Asthma and Allergies in Childhood (ISAAC)

reported a prevalence of rhinitis with itchy eyes (allergic rhi-
Childhood ± atopic

noconjunctivitis) of up to 40% of the population in developed

VKC

±Vernal plaque

countries (La Rosa et al. 2013). The above prevalence figures

Giant papillae
exacerbations

exacerbations

Pseudoptosis

Trantas dots
±Thickened

reflect ocular allergy associated with other coexisting allergic

Oedema

diseases, and not being isolated ocular symptoms. This has

±Ulcer

important clinical implications, as patients usually seek

SPK

medical advice for the coexisting allergic diseases, and the

ocular symptoms are often not fully appreciated or adequately
Follicles and/
IgE-mediated

examined, contributing to the suboptimal management of

or papillae
± Oedema
Persistent

Persistent
PAC

patients with ocular allergy.

Atopic

Although the ISAAC study reported that the prevalence of

e

this condition in developing countries was low, it was not

assessed for isolated ocular allergic conditions. Recent studies
Follicles and/
IgE-mediated
Intermittent

Intermittent

or papillae

have reported prevalence rates of 7.9%, 9.1% and 32% in

SAC

Oedema

Gambia, Ghana, and Nigeria respectively (Abokyi, Koffuor,

Atopic

Ntodie, Kyei, & Gyanfosu, 2012; Malu, 2014; Wade, Iwuora, &
e

Lopez, 2012). In countries with high rates of HIV infection,

such as South Africa, ocular allergies have been reported to be
Presentation

Presentation

Conjunctiva
Background
mechanism
Feature

more prevalent in patients with HIV/AIDS (Visser, 2013).

Allergic

Limbus

Cornea
Eyelids

The impact of ocular allergy can lead to lost economic gain,

missed employment and educational opportunities, and
result in a generally reduced quality of life. Pitt et al. (2004)
EAACI e Johansson et al., 2001

estimated the annual treatment cost per patient to vary

WAO e Johansson et al., 2004

from 64£ to 124£ in Oxfordshire, UK, with a reduction in pro-

ductivity of 2.3 h/week during the pollinic season. A study in
Spain showed an estimated cost of 348.50 V/year for each
Leonardi et al., 2012
Mantelli et al., 2009

La Rosa et al., 2013

Chowdhury, 2013

patient with SAC (Smith et al., 2005), indicating that ocular

allergy is a major public health concern in these countries.
Bielory, 2000

Broide, 2009

While it has been reported that the prevalence of ocular al-

lergy in many other countries has increased over the last 40
Study

years, the costs related to treating it are not available. A

number of questionnaires, validated in the Spanish
 h e a l t h s a g e s o n d h e i d 2 2 ( 2 0 1 7 ) 1 1 2 e1 2 2 115

population, have been developed to explore different aspects and perennial allergies, while preservative-free Lotemax

nchez et al., 2011). It is therefore suggested
of this condition (Sa
nchez et al., 2011).
ointment can be used as an alternative (Sa
that similar questionnaires be developed and validated for
other population groups, including South Africans, to explore 5.2. Perennial allergic conjunctivitis
the impact of ocular allergy. In addition, well-conducted
epidemiological studies are needed to determine the exact Perennial allergic conjunctivitis (PAC) is milder than SAC, and
prevalence, severity and impact of this condition. is a chronic condition that occurs throughout the year, being
induced by exposure to dust, mites, fungi, animal epithelial
and/or occupational allergens (Friedlaender, 2011). PAC af-
5. Pathophysiology and clinical entities fects young adults between 20 and 40 years of age, but has no
gender preference (Friedlaender, 2011). The pathophysiology
Allergic eye diseases generally fall into two main categories of PAC is the same as that of SAC, with patients presenting
namely: IgE-mediated and cell-mediated conditions. Sub- with bilateral itching, tearing and burning sensation
stances such as histamines, bradykinins, serotonins, leuko- (Friedlaender, 2011). There is also conjunctival injection but
trienes, prostaglandins, major histocompatibility complex no corneal involvement (Fig. 1). Blurred vision and photo-
(MHC1), interferons, chemotactic factors and the complement phobia may be due to an alteration in the composition and
systems have been reported to be involved in the patho- instability of the tear film (Bielory & Friedlaender, 2008).
physiology of ocular allergic diseases (Campbell & Mehr, 2015). Identifying potential causes and triggers, and avoiding or
Pathophysiology involves two stages namely: sensitisation limiting exposure to the allergen, are the mainstay treatments
and effector phase reaction. The sensitisation phase results in (Bielory & Friedlaender, 2008). Environmental modifications,
generating a predominantly Th2 immune response with the such as the use of indoor air filters, air conditioning, isolating
subsequent production of IgE antibodies (Abelson, Smith, & pets, and cleaning dust, dander and moulds, are helpful
Chapin, 2003). The second phase, initiated with a second (Friedlaender, 2011). Driving with the windows closed can help
encounter with an antigen, culminates with the activation of to reduce exposure to other types of allergens (Friedlaender,
effector mechanisms, such as the release of histamines and 2011). Artificial tears and cold compresses can help reduce
granulocytes degranulation (Abelson et al. 2003). More than initial ocular symptoms, but many patients require short-term
five decades after being identified as a unique condition, there therapy with a steroid or an NSAID (Friedlaender, 2011).
is still no common understanding of the allergic process or the
terms used to describe the underlying immune pathophysio- 5.3. Vernal keratoconjunctivitis
logical mechanisms of ocular allergy. Research efforts need to
be directed towards understanding the possible underlying Vernal keratoconjunctivitis (VKC) is a self-limiting, chronic
immune patho-mechanisms in the different types of ocular allergic inflammation of the ocular surface that typically af-
allergies. fects young people and is usually more common in warm
tropical climates (Lambiase et al., 2009). It is more frequent in
5.1. Seasonal allergic conjunctivitis males, with an increased incidence of those between 11 and 13
years of age (Lambiase et al., 2009). The symptoms may be
Seasonal allergic conjunctivitis (SAC) is the most common seasonal or perennial, with exacerbations generally in sum-
form of all ocular allergy disease, and is usually triggered by mer or in autumn (Friedlaender, 2011; Lambiase et al., 2009). It
exposure to airborne pollens produced by plants that cause is associated with a history of allergy to pollen or other allergic
hay fever, the signs and symptoms typically occurring in conditions, such as atopic dermatitis, allergic rhinitis, or
spring and summer (La Rosa et al., 2013). The patho- asthma (Friedlaender, 2011; Lambiase et al., 2009).
mechanism involves an IgE-mediated type-I hypersensitivity, The pathophysiology is not precisely known, although two
with the early response clinically lasting for 20e30 min (La hypersensitivity mechanisms (type I and type IV) appear to be
Rosa et al., 2013). The late phase reaction is due to the pres- involved (La Rosa et al., 2013). In the presence of an antigen,
ence of inflammatory cells in the conjunctival mucosa, and is
brought about by activation of vascular endothelial cells,
which express adhesion molecules, such as intercellular
adhesion molecule (ICAM) and vascular cell adhesion mole-
cule (VCAM) (La Rosa et al., 2013). They also express chemo-
kines, such as regulated upon activation normal T cell,
expressed and secreted (RANTES) chemokines, monocyte
chemo attractant protein (MCP), interleukin (IL)-8, eotaxin and
macrophage inflammatory protein (MIP)-1 alpha (La Rosa et al.,
2013). The released histamine and other mediators cause
hyperaemia, itching, burning, swelling and tearing of the eyes,
which often irritate the nasal mucosa (Bielory & Friedlaender,
2008). Topical non-steroidal anti-inflammatory drugs (NSAIDS) Fig. 1 e Seasonal and perennial allergic conjunctivitis:
or steroids, in addition to antihistamine/mast cell stabilisers, conjunctival hyperaemia and oedema (chemosis) involving
are used to treat severe symptoms of SAC. Alrex is the only the bulbar and palpebral conjunctiva (Photograph courtesy
topical steroid approved for the temporary relief of seasonal of Dr MH Sa
nchez).
116 h e a l t h s a g e s o n d h e i d 2 2 ( 2 0 1 7 ) 1 1 2 e1 2 2

lymphocyte activation (predominantly of the Th2 subpopu-

lation) takes place and there is abundant mucosal secretion in
the affected individuals (Friedlaender, 2011; La Rosa et al.,
2013). VKC has three clinical forms: palpebral, limbal, and
mixed, the clinical presentation including severe ocular itch-
ing, redness, swelling, mucous discharge and photophobia (La
Rosa et al., 2013). The most characteristic sign is cobblestone-
like swelling called giant papillae on the upper tarsal con-
junctiva, which can be seen by flipping the upper eyelid (Figs. 2
and 3). IL-4 and IL-13 are involved in forming giant papillae by
inducing extra-cellular matrix production and the prolifera-
tion of conjunctival fibroblasts, with these giant papillae being
filled with neutrophils, plasma cells, mononuclear cells, eo- Fig. 3 e Atopic keratoconjunctivitis: Periorbital skin is
sinophils and mast cells (La Rosa et al., 2013). frequently affected by single or double infraorbital creases
Corneal involvement is in the form of superficial punctate known as DenniseMorgan that are caused by oedema or
thickening (Photograph courtesy of Dr MH Sa
nchez).
keratitis, ulcer formation, neovascularisation, pannus for-
mation and Horner Trantas dots (that consist of clumps of
necrotic eosinophils, neutrophils and epithelial cells). These
eyes are prone to herpetic and fungal keratitis and the pa-
tients also develop atopic cataracts that are anterior shield- & Friedlaender, 2008). AKC patients may also develop atopic
like cataracts (La Rosa et al., 2013). High levels of IgE and cataracts, this being the most debilitating type of allergic
conjunctivitis with high rates of vision impairment (Sa
nchez
mast cell mediators are found in the tears of VKC patients
(Friedlaender, 2011). Oral and topical antihistamines, as well et al., 2011). Topical corticosteroids are the mainstay treat-
as mast cell stabilisers, are useful to treat VKC, particularly ment for this condition, with antihistamine/mast cell stabil-
isers reserved for prophylactic use (Sa
nchez et al., 2011).
after the initial inflammation is minimised (Bielory &
Friedlaender, 2008). Depending on the severity, Lotemax or Topical cyclosporine A has been reported to be effective in
improving the symptoms of AKC (Sa
nchez et al., 2011).
Pred Forte may be used for several weeks, and Alrex for longer,
due to its improved safety profile (Sa
nchez et al., 2011).
5.5. Contact dermatoconjunctivitis

5.4. Atopic keratoconjunctivitis Contact dermatoconjunctivitis (CDC), contact allergy or

allergic contact dermatitis is a type-IV hypersensitivity reac-
Atopic keratoconjunctivitis (AKC) is a bilateral chronic inflam- tion, and occurs through interaction of an antigen with Th1
matory disease of the ocular surface and eyelids (La Rosa et al., and Th2 cell subsets followed by a release of cytokines
2013). Its pathological process involves chronic degranulation (Niederkom, Chen, Mellon, Stevens, & Mayhew, 2010). The
of the mast cells mediated by IgE, and immune mechanisms pathomechanism involves two phases, the first being sensi-
mediated by Th1 and Th2-lymphocytes derived cytokines, eo- tization, where antigen presenting cells process antigen-MHC
sinophils and other inflammatory cells (Leonardi et al., 2007). class II complex interacts with T-lymphocytes, resulting in the
AKC is often associated with atopic co-morbidities such as differentiation of CD4þ T-lymphocytes into memory T-lym-
asthma and eczema, and therefore requires multi-disciplinary phocytes (Niederkom et al., 2010). In the second elucidation
management (Leonardi et al., 2007). Typical ocular findings phase, the interaction between the antigen-MHC-II complex
include mild or severe conjunctival injection and chemosis, and memory T-cells stimulates the proliferation of T-cells and
giant papillae, conjunctival scarring, and Trantas dots (Bielory the release of cytokines (Niederkom et al., 2010).
Allergens are generally simple chemicals that combine
with skin protein to form complete allergens, with examples
including poison ivy, neomycin, latex, atropine and its de-
rivatives (Niederkom et al., 2010). Contact allergy involves the
ocular surface, eyelids and periocular skin, with the initial
sensitization with a contact allergen taking several days
(Niederkom et al., 2010). The reaction may peak 2e5 days after
re-exposure, the delayed reaction being due to the slow
migration of lymphocytes to the antigen depot (La Rosa et al.,
2013). The term ‘delayed hypersensitivity’ is sometimes given
to these reactions, in contrast to ‘immediate hypersensitivity’,
where the rapid development of reactions is mediated by IgE
antibodies (La Rosa et al., 2013). Upon re-exposure to the
allergen, an indurated erythematous reaction slowly develops
Fig. 2 e Vernal keratoconjunctivitis: giant hypertrophic (Figure 4). Withdrawing and avoiding contact with the allergen
papillae in the upper tarsal conjunctiva (Photograph is effective in treating CDC, however, severe cases may require
courtesy of the International Centre for Eye Health). topical or systemic corticosteroids (La Rosa et al., 2013).
 h e a l t h s a g e s o n d h e i d 2 2 ( 2 0 1 7 ) 1 1 2 e1 2 2 117

allergies are usually associated with a watery discharge,

which may contain mucus, making it mucoid in appearance,
often leading to erroneous diagnoses of bacterial conjuncti-

nchez et al., 2011). Whereas the symptom of itching is
vitis (Sa
most closely associated with ocular allergy, some patients
with blepharitis, dry eye, and irritative, nonallergic conjunc-
tivitis also complain of itching (Bielory & Friedlaender, 2008).
Itching that is localised in the conjunctiva and is consistent
points to a diagnosis of allergic conjunctivitis. Patients who
experience itching that is localised to the eyelids or the peri-
Fig. 4 e Contact dermatoconjunctivitis involving the orbital skin may have blepharitis, contact dermatitis, atopic
eyelids and periocular skin (Photograph courtesy of Dr MH eczema, or psoriasis (Bielory & Friedlaender, 2008).

nchez).
Sa Clinicians need to remember the following: if it itches, it is
allergy; if it burns, it is probably dry eye; if the eyelids are stuck
together in the morning, it is bacterial infection. For example,
5.6. Giant papillary conjunctivitis ocular disorders such as VKC, AKC, CDC and GPC are due to
allergy, while viral, bacterial, fungal and parasitic conjuncti-
Giant papillary conjunctivitis (GPC) is not a true ocular al- vitis are of infectious aetiology, and dry eye, episcleritis,
lergy, but rather an irritant phenomenon that induces giant, scleritis, uveitis, pseudotumour and pemphigoid are due to
medium or small papillae in the superior palpebral con- autoimmune disorders (Mantelli et al., 2009). Similarly, the
junctiva (Forister et al., 2009). GPC may occur in the presence differential diagnosis of different types ocular allergy must be
of soft, silicone hydrogel and gas-permeable contact lens established (Table 2).
wear, exposed sutures, scleral and prosthetic contact lenses,
and with floppy eyelid syndrome (Forister et al., 2009). The
close association between contact lens and GPC is believed to 8. Treatment options
be due to the protein build-up on the surface of the lenses, as
well as to their irregular edges that cause irritations Ocular allergy is often misdiagnosed and overlooked because
(Friedlaender, 2011). This condition used to be classified as an its clinical presentation is not specific, and some patients with
allergic phenomenon due to the similarity of conjunctival dry eye, blepharitis, and irritative nonallergic conjunctivitis
changes with vernal conjunctivitis (Figure 2). There is no in- may also complain of similar signs and symptoms. In addition,
crease in IgE or histamine in the tears of GPC patients, and there is usually a lack of concordance between bothersome
the conjunctival tissues may contain mast cells, basophils, or ocular symptoms and clinical findings of ocular allergy on
eosinophils, but not to the extent of an allergic reaction examination. Therefore, the clinical diagnosis of ocular allergy
(Friedlaender, 2011). Itching and redness, mucous discharge, may be challenging and the approach to its management may
contact lens discomfort and intolerance, as well as contact require knowledge about the molecular mechanisms. An
lens coating and excessive movement are common (Forister interdisciplinary medical group, including allergist/immunol-
et al., 2009). Antihistamine/mast cell stabilisers and short- ogist, ear-nose-throat (ENT) specialists, ophthalmologists,
term steroid use (such as Lotemax and Fluorometholone) optometrists, nurses and dermatologist need to work together
are the preferred treatment options (Forister et al., 2009). to improve the ocular and systemic health of the allergic
patient.
Mild forms of ocular allergy may require no treatment,
6. Diagnostic tests particularly if asymptomatic. Treatment options for symp-
tomatic ocular allergy include avoidance of the allergen, cold
The diagnosis of ocular allergy is confirmed by a clinical his- compressors, artificial tears, oral anti-allergies, vasocon-
tory of typical eye symptoms, as well as in-vivo or in-vitro tests strictor/histamine eye drops, mast cell stabilisers eye drops,
directed towards detecting free or cellbound IgE (Friedlaender, NSAIDS, corticosteroids and immunosupressives based on the
2011). Allergy skin prick tests are used to demonstrate an IgE- severity of signs and symptoms (Chowdhury, 2013; La Rosa
mediated reaction and laboratory investigations such as the et al., 2013). Initial attempts at supportive treatment may
radio-allergosorbent test, measures allergen specific IgE anti- need to be followed with medical options or surgery, if the
body (Friedlaender, 2011). Eosinophils in conjunctival scrap- patient finds no relief.
ings are diagnostic of allergy and are elevated in VKC, AKC and
GPC, however, their absence do not rule out ocular allergy 8.1. Supportive
(Friedlaender, 2011).
Cold compresses, irrigation with saline solution or artificial
tears may suffice to relieve mild symptoms of ocular allergy
7. Differential diagnosis (Chowdhury, 2013; La Rosa et al., 2013). Artificial tear substitutes
provide a barrier function and help to improve the first-line
Mild conjunctival hyperaemia, itching and prominent che- defence at the level of conjunctival mucosa by diluting and
mosis are the typical clinical presentation of ocular allergic flushing various allergens and inflammatory mediators that
conditions (Mantelli, Lambiase, & Bonini, 2009). Ocular may be present on the ocular surface (Chowdhury, 2013; La Rosa
118 h e a l t h s a g e s o n d h e i d 2 2 ( 2 0 1 7 ) 1 1 2 e1 2 2

nchez et al., 2011).

Table 2 e Differential diagnosis of ocular allergy (Adapted from Sa
Features SAC PAC VKC AKC CDC GPC
Allergic mechanism IgE-mediated IgE-mediated IgE- and non-IgE- IgE- and non-IgE- Non-IgE-mediated Non-allergic
mediated mediated
Age children/adults children/adults children/adults children/adults Adults adolescents/adults
Gender Predilection none none Males Males none none
Seasonal spring Perennial perennial/summer perennial No spring
History of atopy asthma rhinitis Asthma rhinitis variable Asthma rhinitis variable variable
dermatitis
Discharge watery/mucous Watery watery/ropy/mucous watery/mucous Watery mucous
Vision minimal Minimal mild Severe minimal minimal
Papillary hypertrophy no No 7e8 mm limbus <1 No >1
affected
Peri-ocular skin oedema Oedema oedema dermatitis dermatitis oedema
involvement
Serum IgE elevated Elevated variable greatly elevated variable variable
Eosinophil in frequent very frequent characteristic characteristic not frequent not frequent
conjunctival swab
Goblet cells increased Increased increased decreased variable variable
Skin test positive Positive nonspecific positive variable variable

et al., 2013). Goggles can be worn to decrease the amount of is more suitable for prophylactic and long-term treatment of
allergen reaching the ocular surface (Chowdhury, 2013). chronic ocular allergies than for immediate symptom relief in
acute seasonal conditions (Sorkin & Waard, 1986). N-acetyl-
8.2. Medical aspartyl glutamic acid, or spaglumic acid (NAAGA), is a mast
cell membrane stabiliser, and acts by inhibiting leukotriene
The mainstay of treatment of ocular allergy is anti-allergic
nchez et al., 2011). Lodoxamide acts by inhibiting
synthesis (Sa
drugs, most of which are readily available. These include va- eosinophil activation and degranulation, has been shown to be
soconstrictors, antihistamines, mast cell stabilisers, dual more potent than sodium cromoglycate and NAAGA, and has
mode action drugs, corticosteroids and immunosupressives
nchez et al., 2011).
fewer side effects (Sa
(Leonardi, 2013), each of which will be reviewed.
8.2.3. Multiple action drugs
8.2.1. Vasoconstrictors/antihistamines Several multi-modal anti-allergic agents have been intro-
Over-the-counter preparations that contain a vasoconstrictor duced in recent years, and are becoming the drugs of choice
(usually naphazoline hydrochloride) and an H1 antihistamine for providing immediate symptomatic relief for patients with
(usually antazoline or pheniramine) are useful for reducing ocular allergy. For example, azelastine, bepostatine, epinas-
conjunctival infection, usually providing symptomatic relief tine, ketotifen and olopatadine exert multiple pharmacolog-
without significant side effects (Bielory & Friedlaender, 2008). ical effects such as histamine receptor antagonist, inhibiting
While first-generation oral antihistamines may partially eosinophil activation, mast-cell stabilising and anti-
relieve ocular and nasal symptoms, they may also cause or inflammatory effects (Leonardi, 2013). The agents are well
exacerbate ocular surface dryness, which may impair the tolerated and none are associated with significant ocular
protective barrier provided by the ocular tear film (Bielory & drying effects (Leonardi, 2013).
Friedlaender, 2008). Combining topical antihistamines and
vasoconstrictor may also be useful in the short-term treat- 8.2.4. Non-steroidal anti-inflammatory drugs
ment of mild allergic conjunctivitis (Bielory & Friedlaender, Non-steroidal anti-inflammatory drugs (NSAIDS) can be a
2008). However, adverse effects include burning and stinging useful, short-term treatment option, relieving the pain asso-
on instillation, mydriasis, and rebound hyperaemia or ciated with the allergic inflammatory process (Kari & Saari,
conjunctivitis medicamentosa with chronic use (Sa
nchez 2010). Topical NSAIDS reduce the conjunctival hyperaemia
et al., 2011). Systemic antihistamines reduce tear production and pruritus associated with allergy by interfering with the
from the lacrimal glands and mucin secretion from the goblet synthesis of prostaglandin and leukotrienes by inhibiting the
cells (Sa
nchez et al., 2011) and should therefore never be used cyclooxygenase enzymes (Kari & Saari, 2010). Ketorolac,
in the absence of systemic allergic disease, e.g. rhino- diclofenac, indomethacin and pranoprofen have been shown
conjunctivitis (Sa
nchez et al., 2011). to be effective against itching and conjunctival hyperaemia,
and are valid alternatives to steroids (Kari & Saari, 2010).
8.2.2. Mast cell stabilisers Ketorolac should not be used in asthmatic patients with
Mast cell stabilisers are available over-the-counter and by NSAID intolerance as it has been reported to cause asthmatic
prescription (Leonardi et al., 2012), and are effective for treating crises in these patients (Kari & Saari, 2010).
mild to moderate allergic conjunctivitis. They have a slow
onset of action, and prevent the release of histamines and 8.2.5. Corticosteroids
other chemotactic factors from their storage sites around the For severe allergic conjunctivitis, low-dose corticosteroids eye
eye (Sorkin & Waard, 1986). For example, sodium cromoglycate drops such as luorometholone and loleprednol, which are more
 h e a l t h s a g e s o n d h e i d 2 2 ( 2 0 1 7 ) 1 1 2 e1 2 2 119

potent than mast cell stabilisers, are preferred (Sa
nchez et al., may require short-term treatment with systemic corticoste-
2011). ‘Corticosteroids possess immunosuppressive and anti- roids (e.g. prednisone 1 mg/kg per day) (Leonardi, 2013).
proliferative properties as they hinder the transcription factor
that regulates the transcription of Th2-derived cytokine genes 8.2.6. Immunosupressives
and differentiates activated T-lymphocytes into Th2-lympho- Allergen-specific immunotherapy is an effective treatment in
cytes’ (La Rosa et al., 2013). Patients receiving corticosteroids patients with allergic rhinoconjunctivitis who have IgE anti-
eye drops for longer durations should be closely monitored for bodies to allergens, with cyclosporine and tacrolimus being
glaucoma and cataracts (Leonardi, 2013; Sa
nchez et al., 2011). used in severe cases of VKC and AKC (Leonardi et al., 2012).
Other adverse effects of corticosteroids include delayed wound Cyclosporine inhibits eosinophil infiltration by affecting type
healing and secondary infections (Leonardi, 2013; Sa
nchez IV hypersensitivity, and tacrolimus inhibits the action of T-
et al., 2011). Intranasal corticosteroids have been reported to lymphocytes (Broide, 2009). Cyclosporine and tacrolimus are
be effective for treating nasal symptoms of allergic rhinitis, but useful in steroid resistant cases, with no significant side ef-
their effectiveness for addressing ocular symptoms is incon- fects, except for a burning sensation during administration

nchez et al., 2011). As with topical corticosteroids, the
sistent (Sa having been reported (Utine, Stern, & Akpek, 2010). While
use of intranasal corticosteroids has been associated with immunotherapy is delivered via subcutaneous injection and
elevated intraocular pressure and glaucoma damage sublingual (oral) route, ocular symptoms respond less well
(Bergmann, Witmer, & Slonim, 2009). Severe cases of ocular than nasal symptoms to sublingual route (La Rosa et al., 2011).
allergy that do not respond to any of these topical therapies Oral cyclosporines are however ineffective in treating ocular

nchez et al., 2011).

Table 3 e Drugs used for the treatment of ocular allergic diseases (Adapted from Sa
Class Effect Examples Indications Adverse effect
Vasoconstrictors Reduces hyperaemia Oxymetazoline, PAC, SAC Short duration of action,
Naphazoline, tachyphylaxis mydriasis,
Tetrahydrozoline, ocular irritation,
Phenylephrine hypersensitivity, hypertension
Antihistamines Relieves itching and redness Antazoline, Pheniramine, PAC, SAC Short duration of action,
Alcaftadine, Emedastine, frequently ineffective when
Oxymetazoline, used alone, ocular irritation on
Levocabastine (0.5%) prolonged use
Oral antihistamines Reduces itching, oedema Cetirizine, Loratadine, Severe allergic Dries ocular mucosa, reduce
vasodilatation Ebastine, Levocetirizine, conjunctivitis tear production
Fexofenadine, Mizolastine,
Desloratadine
Levocetirizine,
Fexofenadine, Rupatadine,
Bilastine
Mast cell stabilisers Used for prophylaxis Sodium cromoglycate, PAC, SAC Long-term usage with slow
Lodoxamine, NAAGA onset of action, frequently
ineffective when used alone
Multiple action drugs Relieves redness, itching, Olopatidine (0.1%), PAC, SAC, VKC, AKC Blurred vision, burning and
oedema with immediate effect Ketotifen (0.025%), stinging, unpleasant taste
Nedocromil, following instillation
Epinastine(0.05%), (azelastine)
Azelastine, Bepostatine
NSAIDS Reduces itching and hyperaemia Ketorolac (0.5%), SAC, VKC Transient stinging and burning
Pranoprofen, Fluribuprofen, on instillation, ocular irritation
Nepafenac (0.1%), hypersensitivity reaction
Bromfenac, Pemirolast
potassium, Indomethacin,
Diclofenac (0.1%)
Corticosteroids Downgrades conjunctival Medroxy-progesterone, Severe form of allergic Increases in intraocular
inflammation and reduces Fluorometholone, conjunctivitis pressure (IOP), cataracts
cellular infiltrate Difluprednate (0.05%), for short duration formation, delayed wound
Dexamethasone (0.1%), healing, and increased
Prednisolone (1%), susceptibility to infection
Clobetasone, Rimexolone,
Fluticasone & Mometasone
(topical nasal), Loteprednol
(0.2% & 0.5%), Subcutaneous
injection of triamcinolone
acetonide
Immunosupressives Decreases the severity of signs Cyclosporine (1%, 2%), AKC, VKC Ocular irritation
and symptoms and the need Tacrolimus (0.003%)
for steroids
120 h e a l t h s a g e s o n d h e i d 2 2 ( 2 0 1 7 ) 1 1 2 e1 2 2

allergies (Utine et al., 2010). The drugs, their effects, in- entities that might respond differently to conventional ther-
dications and adverse effects used in various types of ocular apy. Supporting patients with severe ocular allergy requires
allergy treatment are summarised in Table 3. adequate knowledge of the molecular mechanisms involved,
the use of novel treatments and the involvement of an inter-
8.3. Surgical disciplinary treatment group. This will eventually help in
completely understanding, treating and controlling symp-
When medical treatment remains ineffective and visual toms of severe forms of ocular allergy.
function deteriorates, such as in severe cases of AKC and VKC,
surgical treatment should be considered. Procedures such as
excision, cryocoagulation, excision with Mitomycin-C 0.02% or Author's contribution
CO2 laser are used to manage papillary hypertrophy (Tanaka
et al., 2004). Non-healing shield ulcers associated with VKC Khathutshelo Percy Mashige is solely responsible for writing
are best managed by debriding the ulcer base, or using excimer this review article.
laser keratectomy or amniotic membrane graft/free autolo-
gous conjunctival graft, while in cases of mechanical ptosis,
tarsal plate resection is recommended (Tanaka et al., 2004).
Appendix A. Supplementary data

Supplementary data related to this article can be found at

9. Conclusion
http://dx.doi.org/10.1016/j.hsag.2016.07.001.

Although the systematic review retrieved 5200 studies, only 6

met the inclusion criteria (Appendices 1A and 1B). The clas-
sification, nomenclature and epidemiology of ocular allergy Appendix 1A. Flow diagram showing the
have not yet been adequately defined and require further in- selection process for inclusion of studies.
vestigations. The clinical diagnosis of this condition is chal-
lenging due to a wide range of overlapping and comorbid
 h e a l t h s a g e s o n d h e i d 2 2 ( 2 0 1 7 ) 1 1 2 e1 2 2 121

Appendix 1B. A summary of included papers and outcome measures.

Author (s) Title of paper Outcome measures

Classification Epidemiology Pathophysiology Diagnosis Management
and nomenclature
Abelson et al. 2003 Ocular allergic √ √ √ √ √
disease: mechanisms,
disease sub-types,
treatment
Bielory & Friedlaender, 2008 Allergic conjunctivitis √ √ √ √ √
Campbell & Mehr, 2015 Fifty years of √ √ √ √ √
allergy: 1965e2015
Friedlaender, 2011 Ocular allergy √ √ √ √ √

nchez et al., 2011
Sa Allergic conjunctivitis √ √ √ √ √
Schmid & Schmid, 2000 Ocular allergy: causes √ √ √ √ √
and therapeutic options

references the World Allergy Organization, October 2003. Journal of Allergy

and Clinical Immunology, 113, 832e836.
Johansson, S. G., Hourihane, J. O., Bousquet, J., Bruijnzeel-
Koomen, C., Dreborg, S., Haahtela, T., et al. (2001). A revised
Abelson, M. B., Smith, L., & Chapin, M. (2003). Ocular allergic
nomenclature for allergy. An EAACI position statement from
disease: Mechanisms, disease sub-types, treatment. The Ocular
EAACI nomenclature task force. Allergy, 56, 813e824.
Surface, 1, 127e149.
Kari, O., & Saari, K. M. (2010). Updates in the treatment of ocular
Abokyi, S., Koffuor, G. A., Ntodie, M., Kyei, S., & Gyanfosu, L.
allergies. Journal of Asthma and Allergy, 24, 149e158.
(2012). Epidemiological profile and pharmacological
La Rosa, M., Lionetti, E., Leonardi, S., Salpietro, A., Bianchi, L.,
management of allergic conjunctivitis: A study in Ghana.
Salpietro, C., et al. (2011). Specific immunotherapy in children:
International Journal of Pharmaceutical and Biomedical Research, 3,
The evidence. International Journal of Immunopathology and
195e201.
Pharmacology, 24, 68e78.
Bergmann, J., Witmer, M. T., & Slonim, C. B. (2009). The
La Rosa, M., Lionetti, E., Reibaldi, M., Russo, A., Longo, A.,
relationship of intranasal steroids to intraocular pressure.
Leonardi, S., et al. (2013). Allergic conjunctivitis: A
Current Allergy and Asthma Reports, 9, 311e315.
comprehensive review of the literature. Italian Journal of
Bielory, L. (2000). Allergic and immunologic disorders of the eye.
Pediatrics, 39, 18. http://dx.doi.org/10.1186/1824-7288-39-18.
Part II: Ocular allergy. Current Reviews of Allergy and Clinical
Lambiase, A., Minchioti, S., Leonardi, A., Secchi, A. G.,
Immunology, 106, 1019e1032.
Rolando, M., Calabria, G., et al. (2009). Prospective, multicenter
Bielory, L., & Friedlaender, M. H. (2008). Allergic conjunctivitis.
demographic and epidemiological study on vernal
Immunology and Allergy Clinics of North America, 28, 43e58.
keratoconjunctivitis: A glimpse of ocular surface in Italian
Bonini, S. (2006). Allergic conjunctivitis: The forgotten disease.
population. Ophthalmic Epidemiology, 16, 38e41.
Chemical Immunology and Allergy, 91, 110e120.
Leonardi, A. (2013). Management of vernal keratoconjunctivitis.
Broide, D. H. (2009). Immunomodulation of allergic disease.
Ophthalmology and Therapy, 2, 73e88.
Annual Review of Medicine, 60(1), 279e291.
Leonardi, A., Bogacka, E., Fauquert, J. L., Kowalski, M. L.,
Campbell, D. E., & Mehr, S. (2015). Fifty years of allergy:
Groblewska, A., Jedrzejczak-Czechowicz, M., et al. (2012).
1965e2015. Journal of Paediatrics and Child Health, 51, 91e93.
Ocular allergy: Recognizing and diagnosing hypersensitivity
Chowdhury, B. (2013). Allergic conjunctivitis e A review. Dehli
disorders of the ocular surface. Allergy, 67, 1327e1337.
Ophthalmogical Society Times, 19, 41e47.
Leonardi, A., De Dominicis, C., & Motterle, L. (2007).
Critical Appraisal Skills Programme (CASP). (2014). Making sense
Immunopathogenesis of ocular allergy: A systemic approach
of evidence. Available from: http://www.casp-uk.net
to different clinical entities. Current Opinion in Allergy and
Accessed: 20.05.14.
Clinical Immunology, 7, 429e435.
Forister, J. F., Forister, E. F., Yeung, K. K., Ye, P., Chung, M. Y.,
Malu, K. N. (2014). Allergic conjunctivitis in Jos-Nigeria. Nigerian
Tsui, A., et al. (2009). Prevalence of contact lens-related
Medical Journal, 55, 166e170.
complications: UCLA contact lens study. Eye Contact Lens, 35,
Mantelli, F., Lambiase, A., & Bonini, S. (2009). A simple and rapid
176e180.
diagnostic algorithm for the detection of ocular allergic
Friedlaender, M. H. (2011). Ocular allergy. Current Opinion in Allergy
diseases. Current Opinion in Allergy and Clinical Immunology, 9,
and Clinical Immunology, 11, 477e482.
471e476.
Hesselmar, B., Aberg, B., Eriksson, B., & Arberg, N. (2001). Allergic
Niederkom, J. Y., Chen, P. W., Mellon, J., Stevens, C., & Mayhew, E.
rhinoconjunctivitis, eczema, and sensitization in two areas
(2010). Allergic conjunctivitis exacerbates corneal allograft
with differing climates. Pediatric Allergy and Immunology, 12,
rejection by activating Th1 and Th2 alloimmune responses.
208e215.
Journal of Immunology, 184, 6076e6083.
Ibanez, M. D., & Garde, J. M. (2009). Allergy in patients under
Pitt, A. D., Smith, A. F., Lindsell, L., Voon, L. W., Rose, P. W., &
fourteen years of age in Alergologica 2005. Journal of
Bron, A. J. (2004). Economic and quality-of-life impact of
Investigational Allergology and Clinical Immunology, 19, 61e68.
seasonal allergic conjunctivitis in Oxfordshire. Ophthalmic
Johansson, S. G., Bieber, T., Dahl, R., Friedmann, P. S., Lanier, B. Q.,
Epidemiology, 11, 17e33.
Lockey, R. F., et al. (2004). Revised nomenclature for allergy for
Riedi, C. A., & Rosario, N. A. (2010). Prevalence of allergic
global use: Report of the nomenclature review committee of
conjunctivitis: A missed opportunity? Allergy, 65, 131e132.
122 h e a l t h s a g e s o n d h e i d 2 2 ( 2 0 1 7 ) 1 1 2 e1 2 2

nchez, M. C., Ferna

Sa
ndez Parra, B., Matheu, V., Navarro, A., Tanaka, M., Takano, Y., Dogru, M., Fukagawa, K., Asano-Kato, N.,

n
Iba ~ ez, M. D., Da

vila, I., et al. (2011). Allergic conjunctivitis. Journal Tsubota, K., et al. (2004). A comparative evaluation of the
of Investigational Allergology and Clinical Immunology, 21, 1e19. efficacy of intraoperative mitomycin C use after the excision
Schmid, K. I., & Schmid, L. M. (2000). Ocular Allergy: Causes and of cobblestone like papillae in severe atopic and vernal
therapeutic options. Clinical and Experimental Optometry, 83, keratoconjunctivitis. Cornea, 23, 326e329.
257e270. Utine, C. T., Stern, M., & Akpek, E. K. (2010). Clinical review:
Smith, A. F., Pitt, A. D., Rodriguez, A. E., Alio, J. L., Marti, N., Topical ophthalmic use of cyclosporin A. Ocular Immunology
Teus, M., et al. (2005). The economic and quality of life impact and Inflammation, 18, 352e361.
of seasonal allergic conjunctivitis in a Spanish setting. Visser, L. (2013). HIV and the eye. Continuing Medical Education, 31,
Ophthalmic Epidemiology, 12, 233e242. 143e146.
Sorkin, E. M., & Waard, A. (1986). Ocular sodium cromoglycate. An Wade, P. D., Iwuora, A. N., & Lopez, L. (2012). Allergic
overview of its therapeutic efficacy in allergic eye disease. conjunctivitis at Sheikh Zayed regional eye care center,
Drugs, 31, 131e148. Gambia. Journal of Ophthalmic and Vision Research, 7, 24e28.
Takano, Y., Narita, S., & Kobayashi, K. (2004). Seasonal allergic
rhinitis in Hakodote. Nippon Ganka Gakkai Zasshi, 108, 606e611.